Submissions for variant NM_000251.3(MSH2):c.2517T>A (p.His839Gln)

gnomAD frequency: 0.00003  dbSNP: rs267608016

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000524391	SCV000254411	benign	Hereditary nonpolyposis colorectal neoplasms	2023-12-24	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000216575	SCV000275133	likely benign	Hereditary cancer-predisposing syndrome	2019-03-28	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
GeneDx	RCV000479296	SCV000567949	uncertain significance	not provided	2022-05-02	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with personal or family history suggestive of Lynch syndrome (Chao 2008, Tournier 2008); This variant is associated with the following publications: (PMID: 18561205, 18383312, 26333163, 30798936)
Color Diagnostics, LLC DBA Color Health	RCV000216575	SCV000904009	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-11	criteria provided, single submitter	clinical testing	This missense variant replaces histidine with glutamine at codon 839 of the MSH2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). This variant does not impact MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold <= -1.32, PMID: 33357406). This variant has been reported in an individual affected with early onset colorectal cancer (PMID: 18383312) and an individual with a Lynch syndrome associated cancer (PMID: 18561205). This variant has been identified in 5/282852 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Sema4, Sema4	RCV000216575	SCV002534482	uncertain significance	Hereditary cancer-predisposing syndrome	2022-01-02	criteria provided, single submitter	curation
Baylor Genetics	RCV003466966	SCV004196276	uncertain significance	Lynch syndrome 1	2023-09-02	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003997163	SCV004826365	uncertain significance	Lynch syndrome	2023-01-10	criteria provided, single submitter	clinical testing	This missense variant replaces histidine with glutamine at codon 839 of the MSH2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). This variant does not impact MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold <= -1.32, PMID: 33357406). This variant has been reported in an individual affected with early onset colorectal cancer (PMID: 18383312) and an individual with a Lynch syndrome associated cancer (PMID: 18561205). This variant has been identified in 5/282852 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357139	SCV001552507	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The MSH2 p.His839Gln variant was identified in 1 of 28 proband chromosomes (frequency: 0.04) from individuals or families with Lynch syndrome and was absent from 200 control chromosomes; however, the variant was also identified in 5 of 6 of the proband’s healthy relatives (Yuan 2004). The variant was identified in dbSNP (ID: rs267608016 as "With Uncertain significance allele"), ClinVar (1x as likely benign by Ambry Genetics and 3x as uncertain significance by InSight, Invitae, and GeneDx), UMD-LSDB (1x as unclassified variant), Mismatch Repair Genes Variant Database, and Insight Hereditary Tumors Database (9x as class 3). The variant was not identified in COGR, Cosmic, MutDB, or the Zhejiang University Database. The variant was identified in control databases in 5 of 277214 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the European population in 5 of 126712 chromosomes (freq: 0.00004), but not in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The p.His839 residue is conserved in mammals but not in more distantly related organisms and 4 of 5 computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence, however 3 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this information is not predictive enough to assume pathogenicity. Further, functional analysis using the pCAS ex vivo splicing assay demonstrated this variant had no effect on splicing (Tournier 2008). In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.